The Effects of Repeated Opioid Administration on Locomotor Activity: I. Opposing Actions of μ and κ Receptors

Repeated administration of many addictive drugs leads to a progressive increase in their locomotor effects. This increase in locomotor activity often develops concomitantly with increases in their positive-reinforcing effects, which are believed to contribute to the etiology of substance use disorders. The purpose of this study was to examine changes in sensitivity to the locomotor effects of opioids after their repeated administration and to determine the role of μ and κ receptors in mediating these effects. Separate groups of rats were treated with opioid receptor agonists and antagonists every other day for 10 days, and changes in locomotor activity were measured. Repeated administration of the μ agonists, morphine and buprenorphine, produced a progressive increase in locomotor activity during the treatment period, and this effect was blocked by coadministration of the opioid antagonist naltrexone. The κ agonist spiradoline decreased locomotor activity when administered alone and blocked the progressive increase in locomotor activity produced by morphine. The ability of spiradoline to block morphine-induced increases in locomotor activity was itself blocked by pretreatment with the κ antagonist nor-binaltorphimine. Repeated administration of high doses, but not low or moderate doses, of the mixed μ/κ agonists butorphanol, nalbuphine, and nalorphine produced a progressive increase in locomotor activity during the treatment period. Doses of butorphanol, nalbuphine, and nalorphine that failed to produce a progressive increase in locomotor activity when administered alone did so when subjects were pretreated with nor-binaltorphimine. These findings suggest that μ and κ receptors have functionally opposing effects on opioid-mediated locomotor activity and sensitization-related processes.